Tryptoline, also known as 1,2,3,4-tetrahydro-β-carboline (THβC) and tetrahydronorharmane (THN), is a natural organic derivative of β-carboline. It is an alkaloid chemically related to tryptamines. Derivatives of tryptoline have a variety of pharmacological properties and are known collectively as tryptolines.
Use and effects The properties and effects of tryptoline in humans do not appear to be known.
Pharmacology Pharmacodynamics Tryptolines are competitive selective inhibitors of the enzyme monoamine oxidase type A (MAO-A). 5-Hydroxytryptoline and 5-methoxytryptoline are the most active monoamine oxidase inhibitors (MAOIs) with IC50 values of 500nM and 1,500nM, respectively.
Tryptolines are also potent reuptake inhibitors of serotonin and epinephrine, with a significantly greater selectivity for serotonin.
Tryptoline shows weak affinity for the serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors (Ki = 2,510–4,310nM, 3,040–3,900nM, and >10,000nM, respectively). However, it showed a high affinity (Ki) of 28nM against tryptamine-labeled binding sites, whereas affinity for serotonin- and spiperone-labeled sites were much lower (Ki = 6,030nM and 12,030nM, respectively). The drug shows substantially lower affinity for serotonin receptors than tryptamine. Tryptoline is 60-fold more potent in terms of tryptamine binding site interaction than its serotonin reuptake inhibition. The drug is inactive as an agonist of the serotonin 5-HT2B receptor in the rat fundus stomach strip (KB = >3,000nM).
Tryptoline is known to produce various behavioral effects in animals, including analgesia, hypothermia, and hypophagia, as well as antidopaminergic-like reversal of behavioral effects of apomorphine such as hyperlocomotion.
Both tryptoline and pinoline partially substitute for the psychedelic drug LSD in rodent drug discrimination tests. The substitution by tryptoline was found to be blocked by the serotonin receptor antagonist pizotifen and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). In subsequent studies, tryptoline was used as the training drug, and fenfluramine and MDMA fully substituted for tryptoline while LSD and yohimbine partially substituted for tryptoline. Tryptoline likewise substituted for fenfluramine. In a later study, tryptoline failed to substitute for LSD, contradicting previous findings. The non-selective serotonin receptor agonists TFMPP and mCPP fully substituted for tryptoline, whereas serotonin 5-HT1A receptor agonists did not. Neither of the serotonin receptor antagonists pirenperone or metergoline antagonized the tryptoline-mediated discriminative stimulus. It was theorized that the tryptoline cue was mediated by serotonin 5-HT1B receptor activation.
In-vivo formation of tryptolines has been a matter of controversy.
Chemistry Derivatives Tryptoline derivatives have been found to interact with serotonin receptors, such as the serotonin 5-HT1A and 5-HT2 receptors. A couple of notable derivatives, 1-ethyl-6-hydroxytryptoline and 1-(2,4,5-trimethoxyphenyl)-6-chlorotryptoline, are potent and high-efficacy agonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A receptor. Pinoline (6-methoxytryptoline) is another notable tryptoline derivative, acting as a weak serotonin 5-HT2A receptor agonist and as a potent serotonin 5-HT2C receptor agonist among other actions.
See also Substituted β-carboline Norharmane Harmane β-Carboline Harmala alkaloid
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